In many countries prostate cancer is the most common, or the second most common, cancer diagnosed in males. Unless detected early, prostate cancer may spread to the spine and bones of the patient, causing severe pain, bone frailty and death. Between 20 and 30,000 men die each year in the United States, 600 in New Zealand and 2000 in Australia, from prostate cancer. The use of prostate specific antigen (PSA) as a diagnostic biomarker for prostate cancer was approved by the US Federal Drug Agency in 1994. In the nearly two decades since this approval, the PSA test has remained the primary tool for use in prostate cancer diagnosis, in monitoring for recurrence of prostate cancer, and in following the efficacy of treatments. However the PSA test has multiple shortcomings and, despite its widespread use, has resulted in only small changes in the death rate from advanced prostate cancers. To reduce the death rate and the negative impacts on quality of life caused by prostate cancer, new tools are required for more accurate primary diagnosis, for assessing the risk of spread of primary prostate cancers, and for monitoring responses to therapeutic interventions.
The PSA blood test is not used in isolation when checking for prostate cancer; a digital rectal examination (DRE) is usually also performed. If the results of the PSA test or the DRE are abnormal, a biopsy is generally performed in which small samples of tissue are removed from the prostate and examined. If the results are positive for prostate cancer, further tests may be needed to determine the stage of progression of the cancer, such as a bone scan, a computed tomography (CT) scan or a pelvic lymph node dissection.
Currently, the established prognostic factors of histological grade and cancer stage from biopsy results, and prostate-specific antigen level in blood at diagnosis are insufficient to separate prostate cancer patients who are at high risk for cancer progression and require aggressive treatment, from those who are likely to die of another cause.
An important clinical question is how aggressively to treat patients with localized prostate cancer. Treatment options for more aggressive cancers are invasive and include radical prostatectomy and/or radiation therapy. Androgen-depletion therapy, for example using gonadotropin-releasing hormone agonists (e.g., leuprolide, goserelin, etc.), is designed to reduce the amount of testosterone that enters the prostate gland and is used in patients with metastatic disease, some patients who have a rising PSA and choose not to have surgery or radiation, and some patients with a rising PSA after surgery or radiation. Treatment options usually depend on the stage of the prostate cancer. Men with a 10-year life expectancy or less, who have a low Gleason score from a biopsy and whose cancer has not spread beyond the prostate are often not treated. Younger men with a low Gleason score and a prostate-restricted cancer may enter a phase of “watchful waiting” in which treatment is withheld until signs of progression are identified. However, these prognostic indicators do not accurately predict clinical outcome for individual patients.
One feature of prostate cancer is that the phenotype of the disease varies from one patient to another. This is the major problem confronting the physician who seeks to develop the best treatment protocol for each patient. Prostate cancer in different individuals displays very heterogeneous cellular morphologies, growth rates, responsiveness to androgen and its pharmacological blocking agents, and metastatic potential. This heterogeneity in cancer phenotype is reflected in the treatment regimes used by physicians in that different prostate cancer phenotypes are responsive to very different drug regimes.
Treatment options for patients with metastatic prostate cancer are limited in their effectiveness. After development of resistance to androgen-depletion therapy, a patient may proceed to second-line hormonal therapy with ketoconazole, estrogen and Leukine™, and then to docetaxel chemotherapy (Tannock et al., N Engl J. Med. 2004; 351:1502-1512; de Bono et al., N Engl J Med. 2011; 364:1995-2005; de Bono et al., Lancet. 2010; 376:1147-1154; Kantoff et al., N Engl J Med. 2010; 363:411-422). After ketoconazole and docetaxel, the treatment options left for metastatic prostate cancer patients are three further drugs with FDA approval, namely Jevtana™ (cabazitaxel), Provenge™ (Sipuleucel-T) and Zytiga™ (abiraterone), but all are associated with median survivals of less than 2 years. In part, the impact on survival is the result of low response rates, indicating a significant proportion of patients exhibiting de novo resistance to these agents. Other drugs used in the treatment of other cancers, such as Sprycel™, show promise in use against prostate cancer. After the use of FDA-approved drugs, there is a fairly long list of drugs where phase II results suggest possible clinical utility against prostate cancer, including Novantrone™, 5-fluorouracil, doxorubicin, platinum-based drugs, methotrexate and etoposide. However, there is been no reliable way to identify which of these drugs might have the greatest chance at success in treating specific patients.
For each drug application, routine follow-up laboratory tests are used to monitor the health of the patient. These include haemoglobin levels, blood cell count, platelet count, creatinine levels, liver enzymes, alkaline phosphatase and bilirubin. Different patients respond differently to chemotherapy and response rates are low. This is due to the patient's phenotype as revealed by the spectrum of side-effects caused by differences in drug metabolism and pharmacokinetics, polymorphism of detoxification enzymes leading to drug toxicity, and a general suppression of innate and adaptive immunity.
For prostate cancer patients, a major issue is that the androgen receptor numbers in cells increase in many prostate cancers after chemotherapy (Culig et al., J Cell Biochem. 2006; 99:373-381). This is why new drugs, such as Zytiga™ and now Enzalutamide (MDV3100) have been developed to try and circumvent the role of the receptors. Some metastatic and primary prostate cancers retain activation of the androgen receptor in processes that are entirely independent of the androgen ligand. There are a number of mechanisms for this, including up-regulation of androgen receptor expression through amplification of the androgen receptor gene (Visakorpi et al., Nat Genet 1995; 9:401; Chen et al., Nat Med 2004; 10:33; Edwards et al., Br J Cancer 2003; 89:552), increased sensitivity of androgen receptor via overexpression of nuclear co-activators (Gregory et al., Cancer Res 2001; 61:2892.), and splice variant mutations of the receptor (Watson et al., Proc Natl Acad Sci USA 2010; 107:16759; Guo et al., Cancer Res 2009; 69:2305).
While there is a report of the molecular profiling of patients showing overexpression of the androgen receptor after a failed response to docetaxel, and then a dramatic response of measurable disease to second-line hormonal therapy with ketoconazole, estrogen and Leukine™ (Myers et al., Case Rep Oncol. 2012 January-April; 5(1): 154-158), little has been done to try and evaluate why patients fail chemotherapy.
There are currently no effective tests to monitor whether or not a patient is responding to a particular therapy, such as administration of one or more chemotherapeutic agents. The ability to monitor the effectiveness of an on-going treatment regime in a patient would enable a clinician to determine whether the patient should remain on that regime or should be put on a different treatment regime. There thus remains a need in the art for an accurate test for monitoring the efficacy of treatment regimes in subjects with prostate cancer.